A major mechanism by which viruses enter their target cells is the fusion of viral and plasma membranes. With human immunodeficiency virus (HIV), the fusion process involves two envelope glycoproteins, gp120 and gp41, on HIV and two receptors, CD4 and a chemokine receptor, on the target cell. Previously, we have reported that synthetic viral fusion peptides with sequences homologous to those of HIV and herpes simplex viruses, when conjugated with another peptide serving as reporter or antiviral drug, can penetrate cells susceptible to infection by their corresponding viruses. These fusion peptides, like the viruses, require specific receptors for cellular entry. The present project is an attempt to utilize this unique situation to develop an antiviral agent that is not affected by the viruses's ability to mutate. Anti-HIV drugs currently in use fall into two categories: those interfering with HIV replication like the protease or reverse transcriptase inhibitors and those interfering with fusion by binding to chemokine receptors like AMD3100 or to the fusion complex like T20 peptide analogs. Unfortunately, treatment of patients with acquired immunodeficiency syndrome using these drugs invariably encounters drug resistant HIV strains. It thus appears that, to overcome the problem of HIV mutation, the best way is to shut down the patient's own door instead of trying to compete with the ever-changing virus. The basic design in this project is to use the specific recognition properties of the fusion peptide and modify it into a blocker of the receptor. A compound that is being tested on NIH3T3 and HeLa cell lines is a fusion peptide with one amino acid replaced at a strategic position. This peptide has been shown to be ineffective to support fusion but capable of binding to the receptor. Another approach is to link the fusion peptide to another component, such as AMD3100, that binds to a different region on the receptor. The project will be carried out in the future in collaboration with Dr. Kefeng Qin who is conducting research on HIV at the Baltimore campus of the University of Maryland.